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Molecular docking study and antiviral evaluation of 2-thioxo-benzo[g]quinazolin-4(3H)-one derivatives.

Al-Salahi R, Abuelizz HA, Ghabbour HA, El-Dib R, Marzouk M - Chem Cent J (2016)

Bottom Line: The cytotoxicity (CC50), effective concentration (EC50) and the selectivity index (SI) values were determined.Based on their EC50 values, a number of the investigated compounds demonstrated weak to moderate activity relative to their parents.Accordingly, compounds 5-9, 11, 15-18, 21, 22, 24, 25, 27 and 28 were active against CVB4, and compounds 5 and 24 were active against HSV-1 and 2 in comparison to ribavirin and acyclovir, which were used as reference drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh, 11451 Saudi Arabia.

ABSTRACT

Background: The persistent appearance of viral strains that causes a resistant viral infection has led to continuous trials for the design and development of novel antiviral compounds. Benzoquinazoline compounds have been reported to exhibit an interesting antiviral activity. This work aims to study and evaluate the antiviral activity of a newly prepared 2-thioxo-benzo[g]quinazolin-4(3H)-one series against herpes simplex (HSV-1 & 2) and coxsackievirus (CVB4).

Methods: The antiviral activity was performed using the MTT assay, in which Vero cells (obtained from the American Type Culture Collection, ATCC) were propagated in fresh Dulbecco's Modified Eagle's Medium (DMEM) and challenged with 10(4) doses of the virus. Thereafter, the cultures were treated simultaneously with two-fold serial dilutions of the tested compound and incubated at 37 °C for 48 h. Molecular docking studies were done on the CVB4 2A proteinase enzyme using Molegro Virtual Docker software.

Results: The cytotoxicity (CC50), effective concentration (EC50) and the selectivity index (SI) values were determined. Based on their EC50 values, a number of the investigated compounds demonstrated weak to moderate activity relative to their parents. Accordingly, compounds 5-9, 11, 15-18, 21, 22, 24, 25, 27 and 28 were active against CVB4, and compounds 5 and 24 were active against HSV-1 and 2 in comparison to ribavirin and acyclovir, which were used as reference drugs.

Conclusion: The obtained results gave us some useful insights about the characteristic requirements for future trials to build up and design more active and selective antiviral 2-thioxo-benzo[g]quinazolin-4(3H)-one agents.Graphical abstractCompound 24 superimposed with Ribavirin in CV B4 2A Proteinase enzyme (PDB: 1Z8R) active site.

No MeSH data available.


Related in: MedlinePlus

Compound 24 shows hydrogen bonds interactions with CVB4 2A Proteinase enzyme (PDB: 1Z8R) active site
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Fig3: Compound 24 shows hydrogen bonds interactions with CVB4 2A Proteinase enzyme (PDB: 1Z8R) active site

Mentions: Compounds 1–6 had MolDock scores ranging from −81.42 to −84.81 (Table 3). These scores increased from −84.82 to −126.89 in compounds 7–28, and reached the highest levels (−124.852, −124.156 and −126.899) in compounds 10, 18 and 24, respectively. However, compounds 10 and 18 have a 3-methoxybenzyl group at the “R1” position, but they are varied between each other with butyl group in compound 10 and allyl group in compound 18 at the “R” position. Even though, their MolDock scores were high but it did not enhance their antiviral activity. On the other hand, compound 24 that gave the highest MolDock score in this experiment has a phenyl group at “R” position and 3-cyanobenzyl group at “R1” position. Compound 24 made three hydrogen bonds with the amino acid residues (Tyr 89, Asn 19 and Glu 88) with CVB4 2A Proteinase enzyme (PDB: 1Z8R) active site (Fig. 3). Interestingly, the para position of “R1” substituted benzyl group, such as compound 12, did not enhance the MolDock score than the meta position as in compound 10 and 18. This supports the notion that a hydrophobic moiety at the “R” position is important for the protein binding and the wide range of antiviral activity against CVB4 and HSV. We propose that the phenyl group in compound 24 might participate in a non-polar staking interaction. Moreover, the quality of the docking process was attributed to the good overlapping of compound 24 with ribavirin in the active site (Fig. 4). Taking into account the preceding results, S-alkylated products 7–28 demonstrated good interaction with CVB4 with regard to the parent compounds (1–3), along with 9, 21 and 24 that indicate good relation with the biological results in Table 3.Fig. 3


Molecular docking study and antiviral evaluation of 2-thioxo-benzo[g]quinazolin-4(3H)-one derivatives.

Al-Salahi R, Abuelizz HA, Ghabbour HA, El-Dib R, Marzouk M - Chem Cent J (2016)

Compound 24 shows hydrogen bonds interactions with CVB4 2A Proteinase enzyme (PDB: 1Z8R) active site
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4837545&req=5

Fig3: Compound 24 shows hydrogen bonds interactions with CVB4 2A Proteinase enzyme (PDB: 1Z8R) active site
Mentions: Compounds 1–6 had MolDock scores ranging from −81.42 to −84.81 (Table 3). These scores increased from −84.82 to −126.89 in compounds 7–28, and reached the highest levels (−124.852, −124.156 and −126.899) in compounds 10, 18 and 24, respectively. However, compounds 10 and 18 have a 3-methoxybenzyl group at the “R1” position, but they are varied between each other with butyl group in compound 10 and allyl group in compound 18 at the “R” position. Even though, their MolDock scores were high but it did not enhance their antiviral activity. On the other hand, compound 24 that gave the highest MolDock score in this experiment has a phenyl group at “R” position and 3-cyanobenzyl group at “R1” position. Compound 24 made three hydrogen bonds with the amino acid residues (Tyr 89, Asn 19 and Glu 88) with CVB4 2A Proteinase enzyme (PDB: 1Z8R) active site (Fig. 3). Interestingly, the para position of “R1” substituted benzyl group, such as compound 12, did not enhance the MolDock score than the meta position as in compound 10 and 18. This supports the notion that a hydrophobic moiety at the “R” position is important for the protein binding and the wide range of antiviral activity against CVB4 and HSV. We propose that the phenyl group in compound 24 might participate in a non-polar staking interaction. Moreover, the quality of the docking process was attributed to the good overlapping of compound 24 with ribavirin in the active site (Fig. 4). Taking into account the preceding results, S-alkylated products 7–28 demonstrated good interaction with CVB4 with regard to the parent compounds (1–3), along with 9, 21 and 24 that indicate good relation with the biological results in Table 3.Fig. 3

Bottom Line: The cytotoxicity (CC50), effective concentration (EC50) and the selectivity index (SI) values were determined.Based on their EC50 values, a number of the investigated compounds demonstrated weak to moderate activity relative to their parents.Accordingly, compounds 5-9, 11, 15-18, 21, 22, 24, 25, 27 and 28 were active against CVB4, and compounds 5 and 24 were active against HSV-1 and 2 in comparison to ribavirin and acyclovir, which were used as reference drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh, 11451 Saudi Arabia.

ABSTRACT

Background: The persistent appearance of viral strains that causes a resistant viral infection has led to continuous trials for the design and development of novel antiviral compounds. Benzoquinazoline compounds have been reported to exhibit an interesting antiviral activity. This work aims to study and evaluate the antiviral activity of a newly prepared 2-thioxo-benzo[g]quinazolin-4(3H)-one series against herpes simplex (HSV-1 & 2) and coxsackievirus (CVB4).

Methods: The antiviral activity was performed using the MTT assay, in which Vero cells (obtained from the American Type Culture Collection, ATCC) were propagated in fresh Dulbecco's Modified Eagle's Medium (DMEM) and challenged with 10(4) doses of the virus. Thereafter, the cultures were treated simultaneously with two-fold serial dilutions of the tested compound and incubated at 37 °C for 48 h. Molecular docking studies were done on the CVB4 2A proteinase enzyme using Molegro Virtual Docker software.

Results: The cytotoxicity (CC50), effective concentration (EC50) and the selectivity index (SI) values were determined. Based on their EC50 values, a number of the investigated compounds demonstrated weak to moderate activity relative to their parents. Accordingly, compounds 5-9, 11, 15-18, 21, 22, 24, 25, 27 and 28 were active against CVB4, and compounds 5 and 24 were active against HSV-1 and 2 in comparison to ribavirin and acyclovir, which were used as reference drugs.

Conclusion: The obtained results gave us some useful insights about the characteristic requirements for future trials to build up and design more active and selective antiviral 2-thioxo-benzo[g]quinazolin-4(3H)-one agents.Graphical abstractCompound 24 superimposed with Ribavirin in CV B4 2A Proteinase enzyme (PDB: 1Z8R) active site.

No MeSH data available.


Related in: MedlinePlus